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Control of glucose metabolism by PACAP : stimulation of insulin secretion and potentiation of insulin action

PACAP 控制葡萄糖代谢：刺激胰岛素分泌并增强胰岛素作用

基本信息

批准号：
09670052
负责人：
YADA Toshihiko
金额：
$ 1.98万
依托单位：
Kagoshima University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1998
项目状态：
已结题

项目摘要

We examined whether pituitary adenylate cyclase-activating polypeptide (PACAP) serves as an intra-islet regulator of glucose-induced insulin secretion. High glucose-stimulated insulin release from isolated rat islets was attenuated by an antiserum specific for PACAP, but not by nonimmune sera. The islet incubation medium with high glucose possessed a capacity, which was neutralized by the PACAP antiserum, to increase cytosotic Ca^<2+> concentration ([Ca^<2+>]_i) in beta-cells. PACAP antiserum also neutralized the [Ca^<2+>]_i-increasing action of synthetic PACAP, but not VIP and glucagon. In islets and a beta-cell line, MIN6, expression of PACAP mRNA was detected by reverse-transcription polymerase chain reaction (RT-PCR) and biosynthesis of PACAP was detected by metabolic labeling and immunoblotting. Immunoreactivity for PACAP-selective receptor (PAC1-R) was observed in islets. [Ca^<2+>]_i measurements combined with immunocytochemistry with insulin antiserum demonstrated that glucose-u … More nresponsive beta-cells are recruited by PACAP into [Ca^<2+>]_i responses. These results reveal that PACAP is a novel islet substance, which is synthesized and released by islet cells and then) in an autocrine/paracrine manner, potentiates and arouses beta-cell responses to glucose, thereby amplifying glucose-induced insulin secretion in islets.Next, we explored a possible extra-pancreatic action of PACAP.PAC1-R was expressed in the rat fat tissue and an adipocyte cell line, 3T3-Li. PACAP significantly enhanced the insulin-induced 2-deoxyglucose uptake by 333-Li adipocytes. Both insulin receptor beta-subunit and insulin receptor substrate-1 (IRS-1) were tyrosine-phosphorylated by insulin, on which PACAP had no additional effect. In contrast, the insulin-stimulated phosphatidylinositol (PI) 3-kinase activity was further increased by PACAP.The basal 2-deoxyglucose uptake and PI 3-kinase activity were not altered by PACAP.These results indicate that PACAP promotes insulin-induced glucose uptake by increasing PI 3-kinase activity, and reveal that PACAP not only potentiates glucose-induced insulin secretion in islets but also potentiates insulin action in adipocytes. Less

我们检查了垂体腺苷酸环化酶激活多肽（PACAP）是否充当葡萄糖诱导的胰岛素分泌的胰岛内调节剂。 PACAP 特异性抗血清可减弱离体大鼠胰岛的高葡萄糖刺激胰岛素释放，但非免疫血清则不会减弱。具有高葡萄糖的胰岛培养培养基具有增加β细胞中胞质Ca 2+ 浓度([Ca 2+ ]_i)的能力，该能力被PACAP抗血清中和。 PACAP抗血清还中和合成PACAP的[Ca^2+]_i增加作用，但不中和VIP和胰高血糖素。在胰岛和 β 细胞系 MIN6 中，通过逆转录聚合酶链反应 (RT-PCR) 检测 PACAP mRNA 的表达，并通过代谢标记和免疫印迹检测 PACAP 的生物合成。在胰岛中观察到 PACAP 选择性受体 (PAC1-R) 的免疫反应性。 [Ca^<2+>]_i 测量与胰岛素抗血清免疫细胞化学相结合表明，PACAP 将葡萄糖-u 反应性 β 细胞募集到 [Ca^<2+>]_i 反应中。这些结果表明，PACAP是一种新型胰岛物质，由胰岛细胞合成和释放，然后以自分泌/旁分泌的方式增强和激发β细胞对葡萄糖的反应，从而放大葡萄糖诱导的胰岛胰岛素分泌。接下来，我们探索了PACAP可能的胰外作用。PAC1-R在大鼠脂肪组织中表达，并在大鼠脂肪组织中表达。脂肪细胞系，3T3-Li。 PACAP 显着增强了胰岛素诱导的 333-Li 脂肪细胞对 2-脱氧葡萄糖的摄取。胰岛素受体 β 亚基和胰岛素受体底物 1 (IRS-1) 均被胰岛素酪氨酸磷酸化，而 PACAP 对此没有额外作用。相比之下，PACAP 进一步增加胰岛素刺激的磷脂酰肌醇 (PI) 3-激酶活性。PACAP 不会改变基础 2-脱氧葡萄糖摄取和 PI 3-激酶活性。这些结果表明 PACAP 通过增加 PI 3-激酶活性来促进胰岛素诱导的葡萄糖摄取，并揭示 PACAP 不仅增强葡萄糖诱导的葡萄糖摄取胰岛中的胰岛素分泌，而且还增强脂肪细胞中的胰岛素作用。较少的